SUMMARY Alzheimer's disease and related dementias are a major public health problem in the United States and worldwide. Although the etiology is not completely understood most patients with Alzheimer's disease have evidence of vascular pathology, thus there is increasing interest in understanding the vascular contribution to cognitive impairment and Alzheimer's disease. There is a major overlap between the risk factors for vascular disease and those for Alzheimer's, including for instance, type II diabetes and insulin resistance, hypertension, hypercholesterolemia, overweight and smoking. These risk factors are major causes of intracranial vascular disease including atherosclerosis, arteriolosclerosis and cerebral amyloid angiopathy leading to infarcts and microinfarcts. Insulin like growth factor-1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that has pleiotropic effects on metabolism, growth, differentiation and survival. IGF-I and its receptor are expressed in the vasculature and we have shown that IGF-I administration to hypercholesterolemic apoe-/-mice reduced vascular and systemic inflammation, oxidative stress, smooth muscle cell apoptosis and atherosclerosis. We are now testing the anti-atherogenic effects of IGF-I in familial hypercholesterolemic Rapacz pigs, a large animal model that has major advantages over rodent models because of its anatomy and physiology being much more similar to humans. IGF-I is also produced within the central nervous system, crosses the blood brain barrier and has pleiotropic neuroprotective effects. However there is significant controversy regarding the potential role of IGF-I in Alzheimer's disease. While observational studies and some rodent studies have suggested that IGF may have beneficial effects on beta- amyloid accumulation and on the risk for Alzheimer's disease, others have shown contradictory results. Evidence suggests that reduced insulin and IGF-I signaling may play a role in the development of Alzheimer's disease. As with cardiovascular disease, small animal models do not reproduce many features of human neurodegenerative diseases. Neuroanatomical studies of the pig brain have shown a much stronger resemblance between pigs and humans than between rodents and humans. We thus have a unique opportunity to study the effect of IGF-I on intracranial vascular and brain disease including large vessel atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, infarcts and microinfarcts in a novel swine model that develops advanced vascular disease. Correlations will be established between the degree of vascular disease and the hallmarks of Alzheimer's disease, notably, beta-amyloid deposits and neurofibrillary tangles, and exploratory transcriptomic, metabolomic and proteomic analysis of vascular and brain tissues will be performed. The study should provide key insights into the development of cerebrovascular, neurovascular and Alzheimer's disease and lay the groundwork for additional large animal studies and a potential trial of IGF-1 in humans with early-stage cognitive impairment and Alzheimer's disease.